Waldenstrom Macroglobulinemia (WM) remains incurable with a median overall survival of 5-6 years, and most patients succumb to disease progression. Therefore, there is a strong rationale for novel therapies that target aberrant molecular pathways in WM. The PI3K/AKT pathway acts as a critical regulator of apoptosis, cell cycle regulation, and tumor proliferation in many lymphoproliferative malignancies. In addition, the PI3K pathway regulates migration and trafficking in lymphocytes indicating that it may regulate homing in WM. Our preliminary data demonstrate that members of the PI3K pathway are upregulated in WM cells as compared to normal control. Downregulation of AKT by a novel therapeutic agent, Perifosine leads to significant inhibition of proliferation and induction of apoptosis in WM cells in vitro. In addition, our data demonstrate that perifosine inhibits migration and adhesion of WM cells in vitro and homing in vivo. Based on these findings, we propose to study this novel agent in a phase II study along with carefully designed translational research studies. We hypothesize that the AKT inhibitor perifosine will increase the overall response rate in patients with relapsed/refractory WM, and have a significant inhibitory effect on homing and adhesion of WM cells to the bone marrow microenvironment. We will study this hypothesis in 3 specific aims. Aim 1 is to determine the safety, tumor response rate, and duration of response for the AKT inhibitor, perifosine in patients with relapsed/refractory WM. Aim 2 is to determine the mechanisms of response/resistance to perifosine in vivo, and Aim 3 is to determine the role of the PI3K/AKT pathway in the regulation of migration and adhesion in WM. These studies will help define the role of the PI3K/AKT pathway in WM and allow the design of future therapeutic trials targeting this pathway, and combinations of agents with other novel targeted agents. [unreadable] [unreadable] [unreadable]